title: The β2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo.
abstract: Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3-β2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in β2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in β2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the β2 integrin. Importantly, dendritic cell-mediated T-cell activation in vivo was normal in TTT/AAA β2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3-integrin association for lymphocyte functions in vivo; the integrin-kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a shear-free environment.
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
authors.forename: Vicky Louise
authors.initials: VL
authors.lastname: Morrison
authors.forename: Matthew
authors.initials: M
authors.lastname: MacPherson
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.forename: Hwee San
authors.initials: HS
authors.lastname: Lek
authors.forename: Alan
authors.initials: A
authors.lastname: Prescott
authors.forename: Susanna Carola
authors.initials: SC
authors.lastname: Fagerholm
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527818:kindlin-3 protein, mouse; D005982:Glutathione Transferase